The goal of this research program is to develop and apply state-of-the-art computation methods to understand stereoselectivity and to aid in the design of new stereoselective reagents and catalysts. The control of stereoselectivity is an essential feature of efficient synthesis, and many elegant procedures for the control of stereochemistry have been developed. These are critical elements in the synthesis of effective pharmaceutical agents. This renewal of GM36700 is built on the achievements of the last grant period. Collaborations with many synthetic laboratories around the world have kept our attention focused on problems that are central to progress in organic synthesis. The grant has been a training vehicle for a large number of graduate students, postdocs, and visitors to our laboratories from synthetic groups, and these people have become leaders in computational understanding of organic and pharmaceutical chemistry. The specific aims for the new grant period are: Aim 1: Development of quantum mechanical methods to provide accurate predictions of stereoselectivity for large and flexible molecules. Many advances in computational methods and applications are needed to make these practical for the real-time exploration of important organic reactions. Aim 2: Explorations of asymmetric organocatalysis and predictions and testing of new catalysts. Many organocatalysts have been discovered and will be studied theoretically. Newly designed catalysts will be studied by us or our collaborators. Aim 3: Exploration of transition metal catalyzed asymmetric reactions. Studies of Rh, Mo, Ru, Pd, and Ni-catalyzed hydrogenations, allylic substitutions, and asymmetric coupling reactions will increase knowledge of the origins of transition metal catalysis of stereoselective reactions. Aim 4: Collaborative design and testing of new reagents and catalysts for stereoselective reactions. Ongoing collaborations with many synthetic organic chemists and other collaborators likely to develop during the next grant period drive the development of new technology and the increase in understanding of stereoselectivity.